Schwann Cells in Neurofibromatosis Type 2 (NF2)

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DESCRIPTION (provided by applicant): About 10% of all intracranial tumors are schwannomas, benign tumors comprised of Schwann cells with biallelelic NF2 mutations. NF2 mutation or loss is believed to cause schwannoma formation. Several lines of evidence implicate merlin, the NF2 protein, in small G-protein signaling. Biochemical evidence and our analysis of primary schwannoma cells suggest that merlin functions in Rac signaling. While normal Schwann cells are polarized, with one surface attached to axons and the other to basal lamina, schwannoma cells are unassociated with axons. This loss of polarity is likely to arise secondary to altered Rac signaling. Because the relevance of the Rac signaling pathway to Schwann cells is not known, we propose to evaluate a merlin-Rac cascade in Schwann cell growth and tumorigenesis. Our specific hypothesis is that merlin limits the duration of Rac signaling in Schwann cells. We further postulate that deregulated Rac signaling accounts for the failed axon-glial interactions characteristic of schwannomas. We plan to use a combination of gain-of-function and loss-of-function mouse models and primary cells from human schwannomas to test these hypotheses. We believe that analysis of primary schwannoma cells offers a rare opportunity to study a pure population of early stage human cancer cells. The proposed studies are expected to provide insight into regulation of normal axon-glial interactions, and to lead to strategies to understand and ultimately treat human schwannomas.